Cytokine Inflammation and management of FM and CFS

Cytokine Inflammation and Management in Fibromyalgia and Chronic Fatigue Syndrome
by John W. Addington
July 24, 2002

Inflammation in an otherwise healthy person is a natural response to injury or infection and is part of the normal healing process. Chronic inflammation, on the other hand, can reflect an improperly functioning immune system. Many researchers feel that chronic inflammation along with an altered immune system may either be the cause or contribute to fibromyalgia (FM) and chronic fatigue syndrome (CFS) symptoms. Fortunately, some treatment options are emerging to manage such inflammation and thus limit the discomfort and pain brought on by these ailments.

Cytokine Inflammation

Chemical messengers called cytokines form an integral part element of the immune system. As messengers, cytokines tell other immune cells to activate, grow or even die. Dr. Lionel Ivashkiv, a rheumatologist, explains that “cytokines regulate the immune system responses and can drive the inflammatory process.” In this and other ways, cytokines aid white blood cells in fighting infection.

Not all cytokine involvement is positive, however. It is thought that highly elevated cytokine levels found in the brains of Alzheimer's patients contribute to their symptoms. Abnormal cytokine activity in rheumatoid arthritis leads to damaged joints. Cytokine disturbances have been implicated, but not always well understood, in other autoimmune disorders as well.

According to Dr. Ivashkiv, there are hundreds of cytokines and their network of activity is very complicated. He states, "It has become clear that the cytokine networks can be perturbed at different levels and have very significant and strong effects on the overall autoimmune process."

Elevated Cytokines in FM and CFS

Besides inflammation, excess cytokines can bring on flu-like symptoms including fever, achiness, and fatigue. In studies, doctors found that fibromyalgia symptoms temporarily resulted when particular cytokines were administered to persons who did not normally have the syndrome. Additionally, some cytokines are known to increase substance P, which transmits pain messages. Thus, it is no wonder that researchers wanted to know whether cytokine levels were elevated in persons with fibromyalgia.

While the latest research published found some fibromyalgia patients had excessive cytokines, the results are considered preliminary only because of the small number of patients studied. Dr. Daniel Wallace headed up an investigation in Los Angeles discovering that patients sick for over two years were more likely to have high cytokines levels. Although the researchers found altered cytokine production in early-stage fibromyalgia, the cytokines were seen to increase with the duration of the sickness. The authors of this work, published in the July 2001 issue of the journal Rheumatology, conclude that their results underscore "the argument for earlier, aggressive intervention to prevent a chronic pattern from developing."

It has not yet been determined, however, whether elevated cytokines are the direct cause of fibromyalgia or merely secondary to another factor. Factors that could contribute to cytokines increase and be a more direct cause of the ailment are other immune problems, abnormal hormone activity, or sleep disturbances. For example, elevated cytokines levels can be induced through sleep deprivation, so perhaps disordered sleep could be the real root of fibromyalgia.

Immune dysfunction as a contributing cause to the related condition of CFS has also been researched. Dr. Nancy Klimas is an immunologist in Miami who has spent considerable time studying CFS. She explains, "with regard to the immune system, we have a system that is hyperactive but not working properly." As part of this hyperactive state, Dr. Klimas has seen unusually high amounts of cytokines in CFS patients, and she feels that this in turn may cause the hormonal imbalances of such persons.

Other researchers feel the same about this possible cause of CFS, despite the mixed result seen in studies performed. Dr. Stephen Straus writes, "An immune disturbance of some type, though, is in line with one favored theory that many of the symptoms of chronic fatigue syndrome derive from excessive cytokine release."

Management of Cytokine Inflammation

--Drug Therapy

While cytokine related drug therapies are starting to have some benefit for conditions like rheumatoid arthritis, that is not the case yet for FM and CFS. Dr. Roberto Patarca has extensively studied the topic and he says medications are not available "mainly because nobody knows which cytokine system in particular to target and because of the [complexity] of the cytokine network components." But research on this topic continues. And, a number of cytokine altering medications are currently being developed. So, it may be that in the not too distant future, medications to regulate cytokine difficulties for FM and CFS may exist.

--Hydrotherapy

Drs. Charles Lapp and Paul Cheney both recommend hydrotherapy as a means of reducing cytokine levels. They recommend 15-30 minutes of being vertically immersed (standing) in water that is around 85 degrees [Fahrenheit], 2-3 times a week. Dr. Lapp explains, "when the temperature of the water is 85-95 degrees, it is cooler than your body temperature, so you are cooling down the core. When you cool down the core, it cuts down on the cytokines as well, and those cause the flu-like symptoms."

The Life Extension magazine notes that the DHA fish oil is the best documented supplement to suppress certain inflammatory cytokines. Actually, supplements containing any essential fatty acids are very important. These would include evening primrose oil, borage oil, flax seed oil, and Omega 3 and 6 [essential fatty acids]. Other anti-inflammatory supplements include Vitamins B, C, E, and K, and DHEA. Herbs that act as natural inflammation fighters are nettle leaf, boswellia, cat's claw and tumeric.

Dr. Zoltan Rona recommends bovine colostrum as a "powerful immune system modulator—stimulating a sluggish immune system or dampening an overactive immune response." He also encourages the use of digestive enzymes whether pancreatic or plant derived, particularly bromelain, because of how well these supplements counter inflammation.

To stabilize an overactive immune system, Dr. Paul Cheney advocates the use of undenatured whey protein (as in Pro Health's ImmunPlex). Whey protein is useful because of its ability to replenish proper glutathione levels that are low in some with CFS. Dr. Cheney believes that deficient glutathione coupled with excessive cytokines is what promotes activation of harmful microbes like EBV [Epstein-Barr Virus], HHV-6 [Human Herpes Virus-6] as well as chlamydia pneumonia, candida and other mycoplasmas.

In a small study on CFS patients, Cheney found whey protein to be very effective in wiping out these harmful microorganisms. Thus, by raising glutathione levels, undenatured whey protein apparently counteracts some of the damaging effects of excessive cytokines.

--Diet

Diet can play a significant roll in managing cytokine related symptoms. This is true both in what foods are best to consume and those that should be avoided. As to which foods to avoid, many researchers are finding that patients with FM and CFS may have food sensitivities that can aggravate their symptoms. Food sensitivities, also called food intolerance, are not the same as food allergies but can nonetheless contribute to illness.

Research published recently in the Lancet medical journal involved a small group of patients with CFS in Norway, who for over four years had benefited from substantial improvement by dietary exclusion of wheat and milk. After reintroducing these foods into their diets, doctors found a "striking rise" in the patients' cytokine levels along with an increase in abdominal discomfort and joint and muscular pain. These doctors state that "the pronounced increase in release of [particular cytokines], suggests that food intolerance is accompanied by a general immune activation…possibly related to the more general symptoms in these patients."

The foods most likely to be the culprits when it comes to intolerance are wheat, yeast, milk, sugar, peanuts, corn, eggs, citrus, alcohol, caffeine and soy. Various tests can detect food sensitivities but the elimination and challenge method is one of the best means to determine this kind of problem. This involves completely avoiding the suspect food (including traces of it in other foods) for 7-10 days, and then noting if symptoms reoccur when the food is reintroduced into the diet.

Prime foods that can counter cytokine inflammation are coldwater fish such as salmon, trout, mackerel, sardines, swordfish, shark, cod and halibut. These fish are beneficial because of the omega-3 fatty acids they contain. It is good to include flax seed, evening primrose oil, and borage oil in one's diet also because of their anti-inflammatory properties. Additionally, fresh pineapple, fresh papaya, spinach, blueberries, strawberries and onions are useful.

Conclusion

Strong preliminary evidence leads many researchers to believe that excess cytokines may be responsible for CFS and FM symptoms. A degree of relief may be possible through present therapies, supplements and diet regimes. As more research reveals in greater detail the exact nature of immune dysfunction in these ailments, medications will likely be developed to more effectively alleviate cytokine inflammation in CFS and FM.

Mullington, et al., Mediators of Inflammation and Their Interaction with Sleep: Relevance for Chronic Fatigue Syndrome and Related Conditions, Annals of the New York Academy of Sciences, 933:201 (2001)

Patarca, Concise Encyclopedia of Chronic Fatigue Syndrome (2000)

Patarca, Cytokines and Chronic Fatigue Syndrome, Annals of the New York Academy of Sciences, 933:185 (2001)

Note that mold toxin raises a person's cytokine levels. If researchers are looking for something that is annoying the immune system, that is one possibility. Other biological neurotoxins like Lyme toxin raise cytokines, too.

The two people I know who have managed to really avoid mold toxins have said that now they can eat anything. They have no more food intolerances.

Thanks for the replies. I'm not sure if anything has changed since 2002 when this article was written. It seems that despite research on CFS we aren't making any real progress in how this DD is treated. By traditional doctors anyways ... And in some cases, but not all, CFS/FM is more complex than most holistic practitioners are prepared to address.

I have a friend who was just diagnosed with CFS/FM by her traditional doc, given Lyrica, sent to PT and when it didn't work was told that she was just depressed and needed to be on antidepressants.

The really sad part about this is that her doc was my doc who told me how food intolerances can cause multiple symptoms. She didn't say it was the cure for CFS/FM but instead gave me a one page list of symptoms from nuero, skin, digestive, endocrine, etc that could be caused by foods.

I left this doc because she changed her tune and refused to help me when I had such a positive response to eliminating wheat, dairy, soy, etc. IMHO, I think she got her wrist slapped for recommending dietary intervention. So I can't see traditional doctors helping us at this point ...

Hi there Forebearance,

I didn't see any mention of mold toxins in this info but I wouldn't discount the affects of mold or any other toxin on our immune systems ability to process toxins. I wonder how all this fits in with Rich's glutathione depletion / methylation cycle block angle.

Here's another article on how cytokines affect our health. This one goes into detail on how to undo this DD too ... BTW. I tried one of the detox drinks (Metagenics UltraClear) that they are recomending and had an allergic reaction to it. It's rice based too which is bad for hypoglycemia ... so this particular treatment protocal wouldn't work for me. I'm not sure if it could work for others though ...

http://www.chiroweb.com/mpacms/dc/article.php?id=35187

Functional Medicine
By David Brady, DC,CCN,DACBN,ND

Within the past five years, many nutritionally and holistically minded chiropractors have embraced "functional medicine" treatment concepts in dealing with the management of many commonly encountered chronic illnesses, including fibromyalgia, chronic fatigue syndrome and rheumatoid arthritis.

This article is an attempt to introduce, simplify, and summarize many of these seemingly complex concepts for practitioners who have just started to use these concepts, and for those practitioners who have been hearing about this revolutionary approach and have been considering incorporating these therapeutic strategies into their practices.

The functional medicine approach to the treatment of chronic disease is one that is based not on one agent or modality as the curative or palliative solution. It is holistically centered on the principle that restoration of proper cellular metabolism, through reducing cumulative toxic load and oxidative stress to the body, will allow normalization of mitochodrial respiration, cellular energy production, and ultimately to a reduction of the signs and symptoms of chronic disease. While many nutritionally-oriented doctors realize that standard nutritional support protocols alone are quite beneficial for cases of mild to moderate chronic disease, more severe cases often require a more comprehensive functional approach.

This functional medicine philosophy and approach was initially developed for clinical use in chronic fatigue patients with excellent results, and because of the commonality observed in many chronic conditions, it has been used over the years in other disorders with great success, including fibromyalgia, rheumatoid arthritis, and auto-immune disorders.1-8 The seminal work of Bland, Rigden, Cheney, and others in the treatment of chronic fatigue syndrome has served as a successful template, and this approach is now used in the treatment of a broad range of chronic diseases1-7.

The functional medicine philosophy is centered on the premise that a breakdown of the intestinal mucosa by the chronic ingestion of food and water-based toxins, and the use of common prescription and over-the-counter drugs (such as antibiotics and NSAIDS), can lead to dysbiosis and a hyperpermeable intestinal mucosa, or leaky gut syndrome. This intestinal hyperpermeablility can result in the intestinal mucosa failing to act as a selective barrier, leading to the crossing of food-based toxins and partially digested food proteins through the intestinal mucosa and into the systemic blood supply. The eventual result is an increase in food allergies and increased toxic load. (see Figure 1).

This increased toxic load can, over time, lead to increased stress on the liver and its ability to adequately detoxify these substances through phase I and II pathways. This will ultimately result in increased systemic tissue toxicity.

Increased tissue toxicity is thought to be a major trigger for mitochondrial dysfunction, which results in an inability of the body's cells, including the muscle cells, to efficiently utilize oxygen dependant aerobic metabolic pathways. This accounts for the majority of ATP production. Decreased cellular ATP production can account for many (if not all) of the symptoms and signs associated with many chronic disease states, such as chronic fatigue syndrome (CFS) and fibromyalgia (FMS).

Increased intestinal permeability can also result in partially digested medium to large food proteins entering the blood supply and acting as antigens. The resulting antigen-antibody complexes seem to have an affinity for the synovium of articulations, This results in an inflammatory response in the joint linings commonly seen in arthritidies such as rheumatoid arthritis (RA). The main therapeutic agents used initially by standard medical physicians in the treatment of RA are (ironically) NSAIDs. NSAIDs, according to the PDR, result in increased intestinal permeability. Is it possible that the traditional allopathic treatment for arthritidies has only resulted in palliating the patient's symptoms, while actually exacerbating the disease?

The functional medicine therapeutic strategy is, therefore, centered around repairing the intestinal mucosa, correcting any intestinal dysbiosis, providing substances to the body to aid tissue detoxification, reducing oxidative stress, and ultimately promoting a return of normal cellular metabolism. Assessment begins by determining intestinal health and the functional reserve of the liver and its detoxification abilities. This is commonly done with the help of patient symptom questionnaires, such as the a metabolic screening questionnaire and functional laboratory studies, such as the lactulose/mannitol challenge for evaluating intestinal permeability, and the complete digestive stool analysis (CDSA) for detecting markers of digestion, absorption, and colonic flora. Detoxification ability of the liver can be assessed via the caffeine clearance and conjugation metabolite challenge tests, which evaluate phase I (cytochrome P450) and phase II (conjugation) liver detoxification pathways (see Figure 2). These tests are not performed by standard clinical laboratories, but are available through specialized laboratories who offer functional testing.9

Once the data is collected, a treatment program (see Figure 3) is selected, which may include specific nutrients to correct any intestinal hyperpermeability (leaky gut syndrome). Individual nutrients such as L-glutamine, purified hypoallergenic rice proteins, inulin, pantothenic acid, and antioxidants can be used, however, a formulary medicinal food10,11 is usually much easier and more practical to use clinically. Digestion and absorption difficulties suggested on the CDSA can be treated with the temporary use of pancreatic enzymes and HCL (if indicated) in patients without gastritis or ulcers. Dysbiosis, a term used to describe an imbalance of colonic flora, can be addressed by the administration of lactobacillus acidophilus and probiotics such as fructooligosaccharides (FOS).

Any pathogenic bacteria, yeast, or parasites detected on the CDSA should be treated with the prescription (or natural) agents suggested by the sensitivity tests on the CDSA. These may include nonprescription substances such as berberine, garlic, citrus seed extract, artemisia, uva ursi, and others. This program of gut restoration is described by Bland, Rigden, Cheney, and others as the "Four R' approach.3-4.

After intestinal issues have been effectively corrected, upregulation of liver detoxification pathways can be accomplished by providing nutrients which are used in phase I biotransformation and phase II conjugation pathways. These may include individual nutrients such as N-acetyl cysteine, methionine, cysteine, glycine, glutamic acid, glutathione and antioxidant nutrients (see Figure 3). However, the use of a specifically designed formulary medicinal food products are much more practical and efficient to use clinically.

Patients with elevated phase I cytochrome P450 enzyme activity and slow phase II conjugation activity should be treated with antioxidant therapy before detoxification begins. This slows the production of highly toxic biotransformed intermediate molecules which increase oxidative stress on the body.

This should all be combined with a diet which emphasizes fresh foods, and eliminates processed and allergenic foods. This will reduce the patients dietary toxic load (exotoxins), while the intestinal program will reduce gastrointestinal derived toxins (endotoxins). Following a modified elimination diet which eliminates the ingestion of gluten and dairy containing foods, and discontinuing as many drugs as possible, will also help during the detoxification process.

While a more comprehensive and complete discussion of this functional approach is beyond the scope of this article, referring to the cited literature can help further clarify these procedures for the practicing clinician and provide more information on the commercially available formulary products specifically designed for use in this program (1-11).

Avoiding mold toxins means that you try to stay out of buildings that have toxic mold growing in them, and you try to stay away from objects that have been in a place where toxic mold spores were in the air. Mold toxins stick to objects like microscopic specks of tar, and you can't remove them. You can wash off the mold spores, but the toxins have to denature, or wear off over time.

If one has been living in a place where there was toxic mold, and one has developed mold poisoning as a result, then when one moves out one becomes really really sensitive to mold toxins.

Like if you take me for example, after I moved out of my apartment that had a spot of toxic mold in it, and I put my stuff into storage and started over with nothing, I started noticing that some stores made me feel sick, and some objects made me feel sick.

So the basics of mold avoidance, which I have done, are something like:
Move to a place that is the least moldy place you can find.
Put all your possessions in storage and start over with all new stuff.
Be careful that the new stuff isn't covered with mold toxins.
Be careful about what buildings you go in to.
Take a shower and change clothes after you have been in a building that makes you sick.
(Sometimes you have to go into bad buildings, because they are so common.)
Wash your hair at least every evening.
Wash your clothes after one wearing. (the clothes you wear to go places)

It's pretty hard to do, so most people want to make sure they have been poisoned by mold before they go to all the effort.

A couple people, who I mentioned above can eat anything, have taken mold avoidance to extreme lengths. They don't live in buildings at all. One sleeps in a custom RV and one sleeps in a tent. They spend as much time as possible outdoors, in pristine wilderness areas. They even pay attention to mold spores that blow around outside in the air (mold plumes).

Both people feel totally well as long as they avoid toxic mold scrupulously.
I think both people feel that it is worth the effort.
But it is an awful lot to go through in order to feel well.

I'm not sure I have the courage to do it.

Maybe you could call what I'm doing "moderate mold avoidance". I'm not sure if it has helped with food intolerances, because food intolerances have not been a big issue for me. The one thing I can't do is drink alcohol. It's a mycotoxin. I should try some and see if I can stand it better now.

I'm not as up on this angle like you are but I was wondering ... once a person has toxic mold in their bodies, isn't it going to stay there and replicate wherever that person lives ? The same way a virus or bacteria replicates ... From what I understand our weakened bodies are breeding grounds for viruses, bacteria, candida, etc.

So eventually any place that person was living would become moldy too. Can we get toxic mold out of our bodies ?

BTW, I have to wash my hair daily. And I only wear my clothes once too. Even if I just wear them for a short period of time. I wasn't sure if it was from viruses, candida or what ...

From the things I've read and heard, my understanding is that it is pretty rare for toxic mold spores to actually germinate and grow inside a person's body. You would have to have a very weak immune system. There are some species of Aspergillus that are known to be capable of doing this.

As far as I know, I don't have any toxic mold living inside my body. What I have are the neurotoxins that the mold makes. When I breathe in the mold spores, the spores die but the toxins get absorbed. Does that make sense?

So because of my genes, which cause my immune system to not recognize mold toxins as things that need to be attacked and excreted, I have all these toxins circulating around in me. Those are what I'm trying to get rid of by taking stuff to bind to them.

Candida is something else. It's not a toxic mold, just a mold. And its natural environment is our bodies, and we all have some to begin with. So sure, I fight Candida overgrowth all the time, like many of us do.

Wow, so you are already doing some of the stuff I had to learn to do. Washing my hair every day is the hardest thing for me. I have thick hair and it takes about four hours to dry, so it's a pain. Slaya suggested I get a really short haircut. I'm too vain!!! lol

this was most interesting to read, and something i was interested in after seeing an abstract of the whittlemore peterson paper discussing cyto's. although i'm a little brain fogged right now to take it right in.

it seems that the whittlemore peterson institute are from the abstract of their research paper last oct looking at and running tests on the cyto's it seems to me that they are maybe going to try to use these as a test????
i know judy said that they were sending samples around the world and they were all coming back the same.

brain fog prevents me from looking into this in more detail. do you know? did you hear anything on this?